Neuropathic pain is a serious health problem that affects millions of people worldwide and occurs in as much as 7% of the general population. The management of neuropathic pain in patients is complex with an estimated 40-60% of individuals refractory to existing analgesic therapies. The aging population, the diabetes epidemic, and the significant cohorts of cancer and AIDS patients all contribute to the prevalence of intractable neuropathic pain. The large number of affected individuals highlights the pressing need to develop novel therapeutics for this condition. The Mrgpr (Mrg/SNSR) family of G protein-coupled receptors (GPCRs) are expressed in the dorsal root ganglia and play an important role in the modulation of nociception. Intrathecal administration of the endogenous peptide BAM8-22 attenuates neuropathic pain in rodent models through activation of the human MrgprX1 ortholog (mouse: MrgprC11, rat: MrgprC). The therapeutic effects, however, are short lived. On Target Therapeutics has championed a novel technology to develop stable, long acting peptide modulators of GPCRs. These analogs are peptide-linker-lipid conjugates that are membrane anchored to provide local activity with high potency and long-term stability. We have modified endogenous BAM8-22 to generate a higher potency analog that anchors into the cellular membrane and provides local activity. In Aim 1, we propose to generate more stable analogs by modifying specific amino acids that we have already identified. In Aim 2, these 'lipidated stable BAM' constructs will be tested in a mouse model of neuropathic pain (chronic constriction injury). Completion of these Specific Aims will result in th selection of a well-characterized candidate compound for further development. Phase II studies will focus on toxicology, dosing, mode of administration, and testing of the stable BAM analog in a larger animal model. The Phase I efforts will be performed at On Target Therapeutics in conjunction with our research partners at Tufts Medical Center (Dr. Alan Kopin) and Johns Hopkins University (Dr. Xinzhong Dong).